Carbamic acid derivatives

ABSTRACT

The present invention relates to compounds of formula                    
     wherein 
     R 1  signifies hydrogen or lower alkyl; 
     R 2 , R 2′  signify, independently from each other, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; 
     X signifies O, S or two hydrogen atoms not forming a bridge; 
     A 1 /A 2  signify, independently from each other, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; 
     B is a group of formula                    
      wherein 
     R 3  signifies lower alkyl, lower alkenyl, lower alkinyl, benzyl, lower alkyl-cycloalkyl, lower alkyl-cyano, lower alkyl-pyridinyl, lower alkyl-lower alkoxy-phenyl, lower alkyl-phenyl, which is optionally substituted by lower alkoxy, or phenyl, which is optionally substituted by lower alkoxy, or lower alkyl-thienyl, cycloalkyl, lower alkyl-trifluoromethyl or lower alkyl-morpholinyl, 
     Y signifies —O—, —S— or a bond; 
     Z signifies —O— or —S—; 
     or B is a 5-membered heterocyclic group of formulas                    
      wherein 
     R 4  and R 5  signifies hydrogen, lower alkyl, lower alkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the proviso that at least one of R 4  or R 5  has to be hydrogen; as well as to their pharmaceutically acceptable salts. 
     These compounds may be used in the control or prevention of acute and/or chronic neurological disorders such as restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, hypoglycaemia, Alzheimer&#39;s disease, Huntington&#39;s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, cognitive disorders, memory deficits, schizophrenia, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, acute and chronic pain, dyskinesia and depression.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

L-glutamic acid, the most commonly occurring neurotransmitter in theCNS, plays a critical role in a large number of physiological processes.The glutamate-dependent stimulus receptors are divided into two maingroups. The first main group forms ligand-controlled ion channels. Themetabotropic glutamate receptors (mGluR) belong to the second main groupand, furthermore, belong to the family of G-protein-coupled receptors.

At present, eight different members of these mGluRs' are known and ofthese some even have sub-types. On the basis of structural parameters,the different second messager signalling pathways and the differentaffinity to low-molecular weight chemical compounds, these eightreceptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I;

mGluR2 and mGluR3 belong to group II; and

mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first groupcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, schizophrenia, Alzheimer'sdisease, cognitive disorders and memory deficits, as well as chronic andacute pain.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are Huntington's chorea, amyotrophic lateral sclerosis(ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficiency functions, such as e.g. musclespasms, convulsions, migraine, urinary incontinence, nicotine addiction,opiate addiction, anxiety, vomiting, dyskinesia and depression.

SUMMARY OF THE INVENTION

The present invention is concerned with carbamic acid ester derivativesof the formula

wherein

R¹ signifies hydrogen or lower alkyl;

R², R^(2′) signify, independently from each other, hydrogen, loweralkyl, lower alkoxy, halogen or trifluoromethyl;

X signifies O, S or two hydrogen atoms not forming a bridge;

A¹/A² signify, independently from each other, phenyl or a 6-memberedheterocycle containing 1 or 2 nitrogen atoms;

B is a group of formula

 wherein

R³ signifies lower alkyl, lower alkenyl, lower alkinyl, benzyl, loweralkyl-cycloalkyl, lower alkyl-cyano, lower alkyl-pyridinyl, loweralkyl-lower alkoxy-phenyl, lower alkyl-phenyl, which is optionallysubstituted by lower alkoxy, or phenyl, which is optionally substitutedby lower alkoxy, or lower alkyl-thienyl, cycloalkyl, loweralkyl-trifluoromethyl or lower alkyl-morpholinyl;

Y signifies —O—, —S— or a bond;

Z signifies —O— or —S—;

or B is a 5-membered heterocyclic group of formulas

 wherein

R⁴ and R⁵ signifies hydrogen, lower alkyl, lower alkoxy, cyclohexyl,lower alkyl-cyclohexyl or trifluoromethyl, with the proviso that atleast one of R⁴ or R⁵ has to be hydrogen;

as well as with their pharmaceutically acceptable salts.

In particular, the invention relates to compounds of the followingstructures:

wherein the definition of substituents is given above.

These compounds and their salts are novel and are distinguished byvaluable therapeutic properties.

It has surprisingly been found that the compounds of formula I aremetabotropic glutamate receptor modulators, acting as antagonists oragonists.

Objects of the present invention are compounds of formula I and theirpharmaceutically acceptable salts per se and as pharmaceutically activesubstances, their manufacture, medicaments based on a compound inaccordance with the invention and their production as well as the use ofthe compounds in accordance with the invention in the control orprevention of illnesses of the aforementioned kind, and, respectively,for the production of corresponding medicaments.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of formula I in the scope of the present inventionare those, in which A signifies phenyl, X signifies 2 hydrogen atoms notforming a bridge and B signifies the group

wherein Z is O and R³ and Y are described above

The following are examples of such compounds:

diphenylacetyl-carbamic acid butyl ester,

diphenylacetyl-carbamic acid ethyl ester or

diphenylacetyl-carbamic acid pent-4-ynyl ester.

Compounds of formula I, wherein A signifies phenyl, X signifies —O— or—S— and B signifies the group

are further preferred, wherein Z is O and R³ and Y are described above

Examples of such compounds are:

(9H-xanthene-9-carbonyl)-carbamic acid ethyl ester,

(9H-xanthene-9-carbonyl)-carbamic acid butyl ester or

(9H-thioxanthene-9-carbonyl)-carbamic acid butyl ester.

Preferred compounds of formula I in the scope of the present inventionare those, in which A signifies phenyl, X signifies 2 hydrogen atoms notforming a bridge and B signifies a heterocyclic group of the formulas

wherein R⁴ and R⁵ have the significances given above.

Examples of such compounds are:

N-(5-ethyl-oxazol-2-yl)-2,2-diphenyl-acetamide,

N-(5-methyl-oxazol-2-yl)-2,2-diphenyl-acetamide,

2,2-diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)-acetamide.

N-[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenyl-acetamide,

N-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide,

N-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide or

N-(5-methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenyl-acetamide

Preferred are further compounds of formula I, in which A signifiesphenyl, X signifies —O— or —S—; and B signifies a heterocyclic group ofthe formulas

for example the following compounds:

9H-xanthene-9-carboxylic acid oxazol-2-yl-amide,

9H-xanthene-9-carboxylic acid (5-propyl-[1,3,4]oxadiazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (5-ethyl-oxazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (5-methyl-oxazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (5-propyl-oxazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid(5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (4-methyl-oxazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-yl)-amide,

9H-Xanthene-9-carboxylic acid(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-amide,

9H-Xanthene-9-carboxylic acid(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-amide,

9H-xanthene-9-carboxylic acid(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-amide or

9H-xanthene-9-carboxylic acid (5-methyl-[1,2,4]oxadiazol-3-yl)-amide.

The invention embraces all stereoisomeric forms in addition to theracemates.

The term “lower alkyl” used in the present description denotesstraight-chain or branched saturated hydrocarbon residues with 1-7carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl,n-propyl, i-propyl and the like.

The term “lower alkoxy” denotes a lower alkyl residue in the sense ofthe foregoing definition bonded via an oxygen atom.

The term “halogen” embraces fluorine, chlorine, bromine and iodine.

The compounds of formula I and their pharmaceutically acceptable saltscan be manufactured by processes, which comprises

a) reacting a compound of the formula

 with a compound of the formula

 to a compound of formula

 wherein the substituents have the significances given above, or

b) reacting a compound of formula

 with a compound of the formula

 to a compound of formula

 in which G is a suitable leaving group, such as Cl, Br or acyloxy, or acarbonyl chloride equivalent such as a carbonyl-pyrazolide, carbonylimidazole, carbonyl benzotriazole, carbonyloxysuccinimide, or activatedesters such as p-nitrophenylester, pentachlorophenylester and the like,and the other substituents have the significances given above,

c) or reacting a compound of formula

 with a compound of the formula

 to a compound of formula

 or

d) reacting a compound of formula

 with a compound of the formula

 to a compound of formula

 wherein the substituents have the significances set forth above, or

e) reacting a compound of formula

 with a heterocyclic compound of formula

 to give a compound of formula

 wherein B is a 5-membered heterocycle of the formulas

 and wherein the remaining substituents have the significances givenabove, and, if desired, converting a functional group in a compound offormula I into another functional group and, if desired, converting acompound of formula I into a pharmaceutically acceptable salt.

In accordance with process variant a) to a compound of formula III, forexample an alcohol (1-butanol, benzyl alkohol, allyl alkohol,isopropyl-alkohol) in dichloromethane is added a compound of formula II,for example diphenylacetyl isocyanate and the mixture is stirred at roomtemperature.

Compounds of formula IA may be prepared in accordance with processvariant b). A compound of formula V, for example a correspondingurethane or carbamic acid alkyl ester, is reacting with a compound offormula IV, for example with 9H-xanthene-9-carbonyl chloride or bromide,or with an acyloxy derivative of formula IV, or with a carbonyl chlorideequivalent of formula IV, which compounds contain a carbonyl-pyrazolidegroup, a carbonyl imidazole group, a carbonyl benzotriazole group, acarbonyloxysuccinimide group or an activated ester such asp-nitrophenylester, pentachlorophenylester and the like. This reactionis carried out in a solvent, such as pyridine, at room temperature bymethods known in the art.

Furthermore, compounds of formula IA-1 and IA may be prepared inaccordance with process variant c) and d), wherein a compound of formulaVI is reacting with a compound of formula VII or VIII. This reaction iscarried out similar to those, described for process variant b).Compounds of formula IB may be prepared by a reaction of a heterocycliccompound of formula IX with a compound of formula IV in the presence ofN,N-dimethylamino pyridine at a temperature of 0° C. The preferredsolvent is methylene chloride.

The pharmaceutically acceptable salts can be manufactured readilyaccording to methods known per se and taking into consideration thenature of the compound to be converted into a salt. Inorganic or organicacids such as, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid or citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methanesulphonic acid, p-toluenesulphonic acid and the like aresuitable for the formation of pharmaceutically acceptable salts of basiccompounds of formula I. Compounds which contain the alkali metals oralkaline earth metals, for example sodium, potassium, calcium, magnesiumor the like, basic amines or basic amino acids are suitable for theformation or pharmaceutically acceptable salts of acidic compounds.

Scheme 1 gives an overview of the manufacture of the compounds offormula IA. The manufacture of representative compounds of formula I isdescribed in detail in examples 1-30, 32 and 34-43. Scheme 2 describesthe process of manufacture of compounds of formula IB, which process isdescribed in more detail in examples 31, 33 and 44-69.

The substituents have the significances given earlier.

wherein B is a 5-membered heterocyclic compound of formulas

and the remaining definitions of substituents are given above.

The starting materials used in schemes 1 and 2 are known compounds ormay be prepared by methods known per se.

The compounds of formula I and their pharmaceutically acceptable saltsare, as already mentioned above, metabotropic glutamate receptoragonists and/or antagonists and can be used for the treatment orprevention of acute and/or chronic neurological disorders, such aspsychosis, schizophrenia, Alzheimer's disease, cognitive diorders andmemory deficits, as well as acute and chronic pain. Other treatableindications are restricted brain function caused by bypass operations ortransplants, poor blood supply to the brain, spinal cord injuries, headinjuries hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.Further treatable indications are Alzheimer's disease, Huntington'schorea, ALS, dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficient functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesiaand depression.

The compounds of the present invention are group I mGlu receptoragonists and/or antagonist. For example, it has been shown that thecompounds of examples 1-22 and 30-69 show agonistic activities and thoseof examples 23-29 are antagonists. The compounds show activities, asmeasured in the assay described below, of 50 μM or less, typically 1 μMor less, and ideally of 0.5 μM or less.

In the table below are shown some specific activity-data:

Example No. agonist/antagonist IC₅₀ (μM) 10 agonist 0.22 32 agonist 0.1465 agonist 0.4  23 antagonist 6.31 24 antagonist 2.79 25 antagonist 1.38

Test Description

cDNA encoding rat mGlu 1a receptor obtained from Prof. S. Nakanishi(Kyoto, Japan) was transiently transfected into EBNA cells using aprocedure described by Schlaeger et al, New Dev. New Appl. Anim. CellTechn., Proc. ESACT Meet., 15, (1998), 105-112 and 117-120. [Ca²⁺]imeasurements were performed on mGlu 1 a transfected EBNA cells afterincubation of the cells with Fluo-3 AM (0.5 μM final concentration) for1 hour at 37° C. followed by 4 washes with assay buffer (DMEMsupplemented with Hank's salt and 20 mM HERPES. [Ca²⁺]i measurementswere done using a fluorometric imaging plate reader (FLIPR, MolecularDevices Corporation, La Jolla, Calif., USA). When compounds wereevaluated as antagonists they were tested against 10 μM glutamate asagonist.

The inhibition (antagonists) or activation (agonists) curves were fittedwith a four parameter logistic equation giving EC₅₀, and Hillcoefficient using the iterative non linear curve fitting software Origin(Microcal Software Inc., Northampton, Mass., USA).

The compounds of formula I and pharmaceutically acceptable salts thereofcan be used as medicaments, e.g. in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,the administration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be processed with pharmaceutically inert, inorganic or organiccarriers for the production of pharmaceutical preparations. Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts andthe like can be used, for example, as such carriers for tablets, coatedtablets, dragees and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula I ora pharmaceutically acceptable salt thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such medicaments which comprises bringing one ormore compounds of formula I or pharmaceutically acceptable salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical dosage form together with one or more therapeuticallyinert carriers.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferredfor all of the indications described. The daily dosage for an adulthuman being weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

Finally, as mentioned earlier, the use of compounds of formula I and ofpharmaceutically acceptable salts thereof for the production ofmedicaments, especially for the control or prevention of acute and/orchronic neurological disorders of the aforementioned kind, is also anobject of the invention.

EXAMPLE 1

Diphenylacetyl-carbamic acid butyl ester

To a stirred solution of 1-butanol (0.32 ml, 3.49 mmol) indichloromethane (4 ml) was added a solution of diphenylacetyl isocyanate(2.33 ml, 0.5M in CH₂Cl₂, 1.16 mmol) and the mixture was stirred at RTfor 1 h. Removal of the solvent in vacuum left a yellow oil, which waspurified by column chromatography on silica gel (ethyl acetate/hexane1:2) to give the title compound (0.3 g, 83%) as a light yellow solid,m.p. 82-84° C. and MS: m/e=334 (M+Na⁺).

EXAMPLE 2

Diphenylacetyl-carbamic acid benzyl ester

The title compound, white solid, m.p. 100-101° C. and MS: m/e=345 (M⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and benzyl alcohol.

EXAMPLE 3

Diphenylacetyl-carbamic acid allyl ester

The title compound, white solid, m.p. 118-120° C. and MS: m/e=295 (M⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and allyl alcohol.

EXAMPLE 4

Diphenylacetyl-carbamic acid isopropyl ester

The title compound, white solid, m.p. 122-124° C. and MS: m/e=297 (M⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and isopropyl alcohol.

EXAMPLE 5

Diphenylacetyl-carbamic acid tert.-butyl ester The title compound, lightyellow solid, m.p. 160-162° C. and MS: m/e=334 (M+Na⁺) was prepared inaccordance with the general method of example 1 from diphenylacetylisocyanate and tert.-butyl alcohol.

EXAMPLE 6

(9H-Xanthene-9-carbonyl)-carbamic acid ethyl ester

To a stirred solution of urethane (0.82 g, 9.21 mmol) and DMAP (0.05 g,0.41 mmol) in pyridine (10 ml) was added at 0° C. 9H-xanthene-9-carbonylchloride (1.50 g, 6.13 mmol). Stirring was continued at RT for 17 h, thereaction mixture was evaporated and water (50 ml)/sat. NaHCO₃ solution(20 ml) was added. The solid was filtered off and crystallized fromwater and afterwards from EtOH/hexane to give the product (1.22 g, 67%)as a white solid, m.p. 228° C. (dec.) and MS: m/e=298.2 (M+H⁺).

EXAMPLE 7

(RS)-(2-Bromo-9H-xanthene-9-carbonyl)-carbamic acid ethyl ester

The title compound, light brown solid, m.p. 203° C. and MS: m/e=375 (M⁺)was prepared in accordance with the general method of example 6 fromurethane and 2-bromo-9H-xanthene-9-carbonyl chloride.

EXAMPLE 8

(9H-Xanthene-9-carbonyl)-carbamic acid butyl ester

The title compound, white solid, m.p.=180-183° C., MS: m/e=325.4 (M+H⁺)was prepared in accordance with the general method of example 6 from9H-xanthene-9-carbonyl chloride and carbamic acid butyl ester.

EXAMPLE 9

Diphenylacetyl-carbamic acid ethyl ester

The title compound, white solid, m.p. 133° C. and MS: m/e=284.2 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenyl-acetyl isocyanate and ethanol.

EXAMPLE 10

Diphenylacetyl-carbamic acid cyclopropylmethyl ester

The title compound, white solid, m.p.=108° C., MS: m/e=309.4 (M+H⁺) wasprepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and cyclopropyl-methanol.

EXAMPLE 11

Diphenylacetyl-carbamic acid pent-4-ynyl ester

The title compound, white solid, m.p. 109° C. and MS: m/e=321.4 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and pent-4-yn-1-ol.

EXAMPLE 12

Diphenylacetyl-carbamic acid 2-cyano-ethyl ester

The title compound, white solid, m.p. 113° C. and MS: m/e=308.3 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and 3-hydroxy-propionitrile.

EXAMPLE 13

Diphenylacetyl-carbamic acid 3-pyridin-4-yl-propyl ester

The title compound, brown solid, m.p. 147-50° C. and MS: m/e=374.4(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and 3-pyridin-4-yl-propan-1-ol.

EXAMPLE 14

Diphenylacetyl-carbamic acid 3-benzyloxy-propyl ester

The title compound, colorless oil, MS: m/e=403.5 (M+H⁺) was prepared inaccordance with the general method of example 1 from diphenylacetylisocyanate and 3-benzyloxy-propan-1-ol.

EXAMPLE 15

Diphenylacetyl-carbamic acid 2-(3,4-dimethoxy-phenyl) ethyl ester

The title compound, white solid, m.p. 144° C. and MS: m/e=419.5 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and 2-(3,4-dimethoxy-phenyl)-ethanol.

EXAMPLE 16

Diphenylacetyl-carbamic acid (RS)-2-phenyl-propyl ester

The title compound, white solid, m.p. 131° C. and MS: m/e=373.5 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and (RS)-2-phenyl-propan-1-ol.

EXAMPLE 17

Diphenylacetyl-carbamic acid thien-2-yl methyl ester

The title compound, white solid, m.p. 116° C. and MS: m/e=351.4 (M+H⁺)was prepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and thien-2-yl-methanol.

EXAMPLE 18

Diphenylacetyl-carbamic acid cyclopentyl ester

The title compound, white solid, m.p. 120-123° C. and MS: m/e=323.4(MH⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and cyclopentanol.

EXAMPLE 19

Diphenylacetyl-carbamic acid cyclohexyl ester

The title compound, white solid, m.p. 117-119° C. and MS: m/e=337.4(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and cyclohexanol.

EXAMPLE 20

Diphenylacetyl-carbamic acid 4-phenyl-butyl ester

The title compound, light yellow solid, m.p.=118° C. and MS: m/e=387.5(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and 4-phenyl-butan-1-ol.

EXAMPLE 21

Diphenylacetyl-carbamic acid 3,5-dimethoxy-phenyl ester

The title compound, white solid, m.p.=150-152° C. and MS: m/e=391.4(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and 3,5-dimethoxy-phenol.

EXAMPLE 22

Diphenylacetyl-carbamic acid 2,2,2-trifluoro-ethyl ester

The title compound, white solid, m.p.=125-127° C. and MS: m/e=337.3(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and 2,2,2 trifluoro-ethanol.

EXAMPLE 23

(2,2-Diphenyl-propionyl)-carbamic acid methyl ester

The title compound, colorless gum, MS: m/e=297.4 (M+H⁺) was prepared inaccordance with the general method of example 1 from crude2,2-diphenylpropionyl isocyanate and ethanol.

EXAMPLE 24

(2,2-Diphenyl-propionyl)-carbamic acid allyl ester

The title compound, white solid, m.p.=89° C. and MS: m/e=309.4 (M+H⁺)was prepared in accordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and prop-2-en-1-ol.

EXAMPLE 25

(2,2-Diphenyl-propionyl)-carbamic acid butyl ester

The title compound, white solid, m.p.=83° C. and MS: m/e=325.4 (M+H⁺)was prepared in accordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and butan-1-ol.

EXAMPLE 26

(2,2-Diphenyl-propionyl)-carbamic acid cyclopropyl methyl ester

The title compound, white solid, m.p.=125° C. and MS: m/e=323.4 (M+H⁺)was prepared in accordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and cyclopropyl-methanol.

EXAMPLE 27

(2,2-Diphenyl-propionyl)-carbamic acid cyclohexyl ester

The title compound, white solid, m.p.=126° C. and MS: m/e=351.4 (M+H⁺)was prepared in accordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and cyclohexanol.

EXAMPLE 28

(2,2-Diphenyl-propionyl)-carbamic acid 4-phenyl-butyl ester

The title compound, yellow oil, MS: m/e=401.5 (M+H⁺) was prepared inaccordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and 4-phenyl-butan-1-ol.

EXAMPLE 29

(2,2-Diphenyl-propionyl)-carbamic acid 2,2,2-trifluoro-ethyl ester

The title compound, white solid, m.p.=143-145° C., MS: m/e=351.3 (M+H⁺)was prepared in accordance with the general method of example 1 from2,2-diphenylpropionyl isocyanate and 2,2,2-trifluoro-ethanol.

EXAMPLE 30

(9H-Thioxanthene-9-carbonyl)-carbamic acid ethyl ester

The title compound, white solid, m.p.=179-182° C., MS: m/e=314.2 (M+H⁺)was prepared in accordance with the general method of example 6 from9H-thioxanthene-9-carbonyl chloride [U.S. Pat. No. 3,284,449] andurethane.

EXAMPLE 31

9H-Thioxanthene-9-carboxylic acid oxazol-2-ylamide

To a stirred solution of (0.048 g, 0.575 mmol) 2-amino-oxazole[Cockerill & al., Synthesis 591(1976)], and DMAP (0.003 g, 0.03 mmol) inpyridine (2 ml) was added at 0° C. (0.100 g, 0.384 mmol)9H-thioxanthene-9-carbonyl chloride. Stirring was continued at RT for 16h, the reaction mixture was evaporated and water (5 ml)/sat. NaHCO₃solution (2 ml) was added. The solid was filtered off, dissolved indichloromethane, dried (MgSO₄), and concentrated in vaccuo. The crudematerial was purified by column chromatobraphy on silica gel (methylenechloride/ methanol 40:1) to give the product (0.022 g, 18%) as a whitesolid, m.p. 188-191° C. and MS: m/e=309.1 (M+H⁺).

EXAMPLE 32

(9H-Thioxanthene-9-carbonyl)-carbamic acid butyl ester

The title compound, white solid, m.p.=151-154° C., MS: m/e=342.2 (M+H⁺)was prepared in accordance with the general method of example 6 from9H-thioxanthene-9-carbonyl chloride and carbamic acid butyl ester.

EXAMPLE 33

9H-Xanthene-9-carboxylic acid oxazol-2-yl-amide

The title compound, white solid, m.p.=232-235° C., MS: m/e=292 (M⁺) wasprepared in accordance with the general method of example 31 from9H-xanthene-9-carbonyl chloride and 2-amino-oxazole.

EXAMPLE 34

Diphenylacetyl-carbamic acid 2-morpholin-4-yl-ethyl ester

The title compound, white solid, m.p.=135-137° C. and MS: m/e=369.3(M+H⁺) was prepared in accordance with the general method of example 1from diphenylacetyl isocyanate and 2-morpholin-4-yl-ethanol.

EXAMPLE 35

Diphenylacetyl-thiocarbamic acid S-butyl ester

The title compound, white solid, m.p.=99° C. and MS: m/e=327 (M⁺) wasprepared in accordance with the general method of example 1 fromdiphenylacetyl isocyanate and butanethiol.

EXAMPLE 36

[(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-m-tolyl-acetyl]-carbamic acidethyl ester

97 μl (95 mg, 0.80 mmol) Diethylcarbonate and 38 ul (30 mg, 0.50 mmol)isopropanol were dissolved in 2 ml of absolute THF. The solution wascooled to 0° C. and 29 mg (0.67 mmol) sodium hydride dispersion (55% inmineral oil) was added. Then 164 mg (0.50 mmol)3-chloro-5-trifluoromethyl-2-pyridyl-3-methylphenylacetamide in portionsat 0° C. After stirring for 1 h at 0° C., the reaction was allowed towarm up to room temperature and stirred overnight. Workup in the usualmanner with ammonium chloride solution and ethyl acetate yielded ayellow oil which was purified by flash chromatography on silicagel usinga 5:1 mixture of hexane and ethyl acetate as eluant. One obtains 14.1 mg(0.035 mmol, 7%) of[(3-chloro-5-trifluoromethyl-pyridin-2-yl)-m-tolyl-acetyl]-carbamic acidethyl ester as a white solid, m.p.=146-147° C., MS: m/e=401.3 (M+H).

EXAMPLE 37

9H-Xanthene-9-carbonyl)-carbamic acid cyclopropylmethyl ester

The title compound, white solid, m.p.=183-185° C., MS: m/e=323 (M⁺) wasprepared in accordance with the general method of example 36 from9H-xanthene-9-carbonyl chloride and carbamic acid cyclopropylmethylester.

EXAMPLE 38

(4-Trifluoromethyl-9H-xanthene-9-carbonyl)-carbamic acid ethyl ester

The title compound, white solid, m.p.=196-198° C., MS: m/e=365 (M⁺) wasprepared in accordance with the general method of example 36 from4-trifluoromethyl-9H-xanthene-9-carbonyl chloride and carbamic acidethyl ester.

EXAMPLE 39

Cyclopropanecarboxylic acid diphenylacetyl-amide

To a stirred and cooled (0° C.) solution of 2,2-diphenylacetamide (500mg, 2.36 mmol) in THF (20 ml) was added sodium hydride (95 mg, 2.36mmol; 60%) and the mixture was stirred at RT for 0.5 h. Thencyclopropanecarboxylic acid chloride (247 mg, 2.36 mmol) dissolved inTHF (5 ml) was added dropwise at RT and the solution was stirred at RTfor 20 h. The reaction mixture was poured into sat. NaHCO₃ solution (50ml) and extracted with ethyl acetate (2×70 ml). The combined organiclayers were washed with brine (50 ml), dried (MgSO₄) and evaporated.Further purification by column chromatography (toluene/ethyl acetate19:1) yielded the product which was recrystallized from ethylacetate/hexane to give a white solid (133 mg, 20%), m.p. 178° C. and MS:m/e=279 (M⁺).

EXAMPLE 40

9H-Xanthene-9-carboxylic acid butyryl-amide

The title compound, white solid, m.p. 222° C. and MS: m/e=295 (M⁺) wasprepared in accordance with the general method of example 39 from9H-xanthene-9-carboxylic acid amide and propanecarboxylic acid chloride.

EXAMPLE 41

N-Diphenylacetyl-butyramide

The title compound, white solid, m.p. 205° C. and MS: m/e=281 (M⁺) wasprepared in accordance with the general method of example 39 from2,2-diphenylacetamide and propanecarboxylic acid chloride.

EXAMPLE 42

Pentanecarboxylic acid diphenylacetyl-amide

The title compound, white solid, m.p. 87° C. and MS: m/e=309 (M⁺) wasprepared in accordance with the general method of example 39 from2,2-diphenylacetamide and pentanecarboxylic acid chloride.

EXAMPLE 43

Pentanoic acid diphenylacetyl-amide

The title compound, white solid, m.p. 83° C. and MS: m/e=296.3 (M+H⁺)was prepared in accordance with the general method of example 39 from2,2-diphenylacetamide and butanecarboxylic acid chloride.

EXAMPLE 44

9H-Xanthene-9-carboxylic acid (5-propyl-[1,3,4]oxadiazol-2-yl)-amide

44a) To a solution of 76 mg (0.60 mmol, 1.2 equiv.)5-propyl-[1,3,4]oxadiazol-2-ylamine and 6 mg (0.05 mmol, 0.1 equiv.) ofN,N-dimethylamino pyridine in 2 ml of dry pyridine was added a solutionof 122 mg (0.5 mmol) 9-xanthene-carboxylic acid chloride in 1.22 ml ofmethylene chloride dropwise at 0° C. The mixture was stirred 3-4 h at 0°C. and then at room temperature overnight. The mixture was poured into awell stirred mixture of 50 ml of ethyl acetate and 50 ml of water. Theorganic phase was separated. The aqueous phase was extracted twice with25 ml of ethyl acetate. The combined organic phases were washed twicewith 25 ml of water, and concentrated. The residue was taken up in c.a.25 ml of ethyl acetate and evaporated to dryness. The crude product (167mg, light yellow solid) yielded, after recristallisation from ethanol 62mg (0.185 mmol, 37%) of 9H-xanthene-9-carboxylic acid(5-propyl-[1,3,4]oxadiazol-2-yl)-amide as white cristals, m.p. 215-216°C. and MS: m/e=335 (M⁺).

44b) The 5-propyl-[1,3,4]oxadiazol-2-ylamine used in the above reactionwas obtained as follows:

To a solution of 5.0 g (47.0 mmol) cyanogen bromide in 50 ml of methanolwas added dropwise over a period of 30 min a solution of 4.80 g (47.0mmol) butyric acid hydrazide in 50 ml of methanol. The mixture was thenrefluxed for 15 min, and then concentrated in vacuo till cristallisationbegan. The cristals (9 g) were filtered off, taken up in 60 ml ofethanol. Then 5 g of finely powdered potassium carbonate were added andthe suspension was stirred for 5 min at room temperature. The resultingorange suspension was filtered, and the filtrate was concentrated invacuo. The resulting orange powder (5.5 g) was purified by flashchromatography on silicagel with a 80:10:1 mixture of methylenechloride/methanol/28% ammonia as eluent to yield 3.95 g (31.1 mmol, 66%)of 5-propyl-[1,3,4]oxadiazol-2-ylamine as white cristals, MS: m/e=127(M⁺).

EXAMPLE 45

2,2-Diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)-acetamide.

The title compound, viscous oil and MS: m/e=322.4 (M+H⁺) was prepared inaccordance with the general method of example 44a from5-propyl-[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acidchloride.

EXAMPLE 46

9H-Xanthene-9-carboxylic acid [1,3,4]oxadiazol-2-ylamide.

The title compound, white solid, m.p. 239-240° C. and MS: m/e=293 (M⁺)was prepared in accordance with the general method of example 44a from[1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride. The[1,3,4]oxadiazol-2-ylamine, white solid, MS: m/e=85 (M⁺) used in theabove reaction was prepared in accordance with the general method ofexample 44b from formic acid hydrazide and cyanogen bromide.

EXAMPLE 47

N-[1,3,4]Oxadiazol-2-yl-2,2-diphenyl-acetamide.

The title compound, light yellow solid, m.p. 131-132° C. and MS:m/e=279.2 (M⁺) was prepared in accordance with the general method ofexample 44a from [1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acidchloride.

EXAMPLE 48

9H-Xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)-amide.

48a) 500.5 mg (1.64 mmol)(3.5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 186.8 mg(1.64 mmol) 5-ethyl-[1,3,4]oxadiazol-2-ylamine were suspended in 1.5 mlDMF and stirred for 6 h at 130°. The reaction mixture was allowed tocool to room temperature and 5 ml of acetone were added. After stirringfor 5 min, the product was filtered, washed with acetone and dried invaccuo to yield 219.5 mg of 9H-xanthene-9-carboxylic acid(5-ethyl-[1,3,4]oxadiazol-2-yl)-amide as a white solid, m.p. 256-257° C.and MS: m/e=321.2 (M⁺) 48b) The 5-ethyl-[1,3,4]oxadiazol-2-ylamine usedin the above reaction was obtained as follows:

To a solution of 6.3 g propionic acid hydrazide (72 mmol) in 50 ml ofwater was added 34 g of saturated potassium bicarbonate solution (75mmol) and a solution of 7.7 g (72 mmol) of cyanogen bromide in 60 ml ofwater. The temperature rises from 22° C. to 32° C. and carbon dioxideevolves. After 30 min white cristals began to appear. The whitesuspension is stirred for 3 h and left to stand overnight. The reactionmixture was evaporated to dryness in vacuo. The crude product isrecristallised from 20 ml of water. The product is filtered, washed witha small amount of ice-cold water and dried in vacuo. One obtains 6.1 g(54 mmol, 75%) of 5-ethyl-[1,3,4]oxadiazol-2-ylamine as a white solid,m.p. 174-175° C. and MS: m/e=113.1 (M⁺).

48c) The (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone used inthe above reaction was obtained as follows: 2.6 g (11 mmol)9-xanthenecarboxylic acid hydrazide was suspended in 2.5 ml of water. 10ml of 2N HCl solution was added. To the thick white suspension was added30 ml of ethanol and the suspension was heated to 65° C. and thenallowed to cool to room temperature. To the resulting light yellowsolution was added 1.1 g (11 mmol) of acetylacetone with vigourousstirring. The temperature rises to 30° C. with formation of whitecristals after about 2 min. Stirring was continued for 15 min at roomtemperature and a further 15 min at 0° C. The product was filtered andwashed with −20° C. ethanol. The crude product was recristallised from15 ml of ethanol to yield 2.80 g (9.2 mmol. 84%) of(3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone as whitecristals, m.p. 114-115° C. and MS: m/e=304.1 (M⁺).

EXAMPLE 49

N-(5-Ethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 123-125° C. and MS: m/e=308.2(M+H⁺) was prepared in accordance with the general method of example 48afrom 1-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone and5-ethyl-[1,3,4]oxadiazol-2-ylamine.

The 1-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone, white solid,m.p. 91-92° C. and MS: m/e=291.2 (M+H⁺) used in the above reaction wasprepared in accordance with the general method of example 48c from2,2-diphenylacetic acid hydrazide [Chem. Zentralblatt. 100, 2414(1929)]and acetylacetone.

EXAMPLE 50

9H-Xanthene-9-carboxylic acid (5-methyl-[1,3,4]oxadiazol-2-yl)-amide.

The title compound, white solid, m.p. 261-263° C. and MS: m/e=307.1 (M⁺)was prepared in accordance with the general method of example 44a from5-methyl [1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acidchloride.

The 5-methyl[1,3,4]oxadiazol-2-ylamine, white solid. MS: m/e=99 (M⁺)used in the above reaction was prepared in accordance with the generalmethod of example 48b from acetic acid hydrazide and cyanogen bromide.

EXAMPLE 51

N-(5-Methyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 160-161° C. and MS: m/e=293.1 (M⁺)was prepared in accordance with the general method of example 44a from5-methyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.

EXAMPLE 52

9H-Xanthene-9-carboxylic acid(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-amide.

The title compound, white solid, m.p. 233-234° C. and MS: m/e=337.1(M+H⁺) was prepared in accordance with the general method of example 48afrom (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.

The 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine, white solid, m.p.113-114° C. and MS: m/e=129.2 (M⁺) used in the above reaction wasprepared in accordance with the general method of example 48b frommethoxyacetic acid hydrazide [J. Org. Chem. USSR, 6(1), 93(1970)] andcyanogen bromide.

EXAMPLE 53

N-(5-Ethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 138-140° C. and MS: m/e=324.3(M+H⁺) was prepared in accordance with the general method of example 44a2,2-diphenylacetic acid chloride and5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.

EXAMPLE 54

9H-Xanthene-9-carboxylic acid[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amide.

The title compound, white solid, m.p. 204° C. and MS: m/e=351.1 (M+H⁺)was prepared in accordance with the general method of example 44a from(3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.

The [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine, white solid, m.p.105-106° C. and MS: m/e=143.1 (M⁺) used in the above reaction wasprepared in accordance with the general method of example 48b from3-methoxypropionic acid hydrazide [U.S. Pat. No. 3,441,606] and cyanogenbromide.

EXAMPLE 55

N-[5-(2-Methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 114-115° C. and MS: m/e=338.2(M+H⁺) was prepared in accordance with the general method of example 44afrom 2,2-diphenylacetic acid chloride and[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.

EXAMPLE 56

9H-Xanthene-9-carboxylic acid(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-amide.

The title compound, white solid, m.p. 246-248° C. and MS: m/e=333.1(M+H⁺) was prepared in accordance with the general method of example 48afrom (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine [J. Med. Pharm. Chem. 5,617(1962)].

EXAMPLE 57

N-(5-Cyclopropyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 159-160° C. and MS: m/e=320.3(M+H⁺) was prepared in accordance with the general method of example 44afrom 2,2-diphenylacetic acid chloride and5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine.

EXAMPLE 58

9H-Xanthene-9-carboxylic acid(5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-amide.

The title compound, white solid, m.p. 234-236° C. and MS:m/e=347.1(M+H⁺) was prepared in accordance with the general method ofexample 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanoneand 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.

The 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine, white solid, m.p.140-141° C. and MS: m/e=139 (M⁺) used in the above reaction was preparedin accordance with the general method of example 48b fromcyclopropanecarboxylic acid hydrazide [J. Chem. Soc. Perkin Trans. 2,1844(1974)] and cyanogen bromide.

EXAMPLE 59

N-(5-Cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 158-159° C. and MS: m/e=334.3(M+H⁺) was prepared in accordance with the general method of example 44afrom 2,2-diphenylacetic acid chloride and5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.

EXAMPLE 60

9H-Xanthene-9-carboxylic acid(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-amide.

The title compound, white solid, m.p. 220-223° C.(decomp.), and MS:m/e=362.2 (M+H⁺) was prepared in accordance with the general method ofexample 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanoneand 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamine [U.S. Pat. No.2,883,391].

EXAMPLE 61

N-(5-Trifluoromethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 149-150° C. and MS: m/e=347.2 (M⁺)was prepared in accordance with the general method of example 44a from5-trifluoromethyl[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acidchloride.

EXAMPLE 62

9H-Xanthene-9-carboxylic acid (5-ethyl-oxazol-2-yl)-amide.

The title compound, white solid, m.p. 212-213° C. and MS: m/e=320.1 (M⁺)was prepared in accordance with the general method of example 44a from5-ethyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and 9-xanthene-carboxylicacid chloride.

EXAMPLE 63

N-(5-Ethyl-oxazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, white solid, m.p. 148-149° C. and MS: m/e=307.3(M+H⁺) was prepared in accordance with the general method of example 44afrom 5-ethyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.

EXAMPLE 64

9H-Xanthene-9-carboxylic acid (5-methyl-oxazol-2-yl)-amide.

The title compound, white solid, m.p. 217-220° C. and MS: m/e=306.1 (M⁺)was prepared in accordance with the general method of example 44a from5-methyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and9-xanthene-carboxylic acid chloride.

EXAMPLE 65

N-(5-Methyl-oxazol-2-yl)-2,2-diphenyl-acetamide.

The title compound, off-white solid, m.p. 166-168° C. and MS: m/e=292.2(M⁺) was prepared in accordance with the general method of example 44afrom 5-methyl-oxazol-2-ylamine and 2,2-diphenyl acetic acid chloride.

EXAMPLE 66

9H-Xanthene-9-carboxylic acid (5-propyl-oxazol-2-yl)-amide.

66a) The title compound, white solid, m.p. 203-205° C. and MS: m/e=334.1(M⁺) was prepared in accordance with the general method of example 44afrom 5-propyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and9-xanthene-carboxylic acid chloride.

66b) The 5-propyl-[1,3,4]oxadiazol-2-ylamine used in the above reactionwas obtained as follows: 21.8 g (0.132 mol) of 2-bromobutyraldehyde[Chem. Ber., 70, 1898(1937)] was dissolved in 67.5 ml of a 4:3 mixtureof DMF and water. Urea, 8.77 g (0.145 mol) was added with stirring. Theclear colorless solution was stirred for 16 h at 105° C. The resultinglight yellow solution is cooled to 0° C. and 10 ml of 45% Sodiumhydroxide solution was added. The solution turns dark yellow (pH 12).100 ml of brine is added and the solution is extracted five times with100 ml of a 9:1 mixture of methylene chloride and methanol. The combinedorganic phases were concentrated to yield 15.62 g of a reddish brown oilwhich was purified by flash chromatography on silicagel with a 9:1mixture of methylene chloride and methanol as eluent. One obtains 6.2 g(0.049 mol. 37%) of 5-5-propyl-oxazol-2-ylamine as a yellow oil whichwas directly used without further purification, MS: m/e=126.1 (M⁺).

EXAMPLE 67

2,2-Diphenyl-N-(5-propyl-oxazol-2-yl)-acetamide.

The title compound, white solid, m.p. 122° C. and MS: m/e=320.2 (M⁺) wasprepared in accordance with the general method of example 44a from5-propyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.

EXAMPLE 68

9H-Xanthene-9-carboxylic acid (4-methyl-oxazol-2-yl)-amide.

The title compound, light yellow solid, m.p. 219-222° C. and MS:m/e=306.1 (M⁺) was prepared in accordance with the general method ofexample 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanoneand 5-methyl-oxazol-2-ylamine [DE 2459380].

EXAMPLE 69

N-(4-Methyl-oxazol-2-yl)-2 2-diphenyl-acetamide.

The title compound, white solid, m.p. 209-21 1° C. and MS: m/e=306.1(M⁺) was prepared in accordance with the general method of example 48afrom (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and5-methyl-oxazol-2-ylamine.

EXAMPLE 70

N-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide

The title compound, white solid, m.p. 215° C. and MS: m/e=293 (M⁺) wasprepared in accordance with the general method of example 44a from3-methyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966),1430-1432) and 2,2-diphenylacetic acid chloride.

EXAMPLE 71

9H-Xanthene-9-carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-yl)-amide

The title compound, white solid, m.p. 208° C. and MS: m/e=307 (M⁺) wasprepared in accordance with the general method of example 44a from3-methyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acidchloride.

EXAMPLE 72

N-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide

The title compound, white solid, m.p. 163° C. and MS: m/e=219 (M⁺) wasprepared in accordance with the general method of example 44a from3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966),1430-1432) and 2,2-diphenylacetic acid chloride.

EXAMPLE 73

9H-Xanthene-9-carboxylic acid(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-amide

The title compound, white solid, m.p. 275° C. and MS: m/e=333 (M⁺) wasprepared in accordance with the general method of example 44a from3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acidchloride.

EXAMPLE 74

N-(5-Methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenyl-acetamide

The title compound, white solid, m.p. 153° C. and MS: m/e=293 (M⁺) wasprepared in accordance with the general method of example 44a from5-methyl-[1,2,4]oxadiazol-3-ylamine (EP 413545) and 2,2-diphenylaceticacid chloride.

EXAMPLE 75

9H-Xanthene-9-carboxylic acid (5-methyl-[1,2,4]oxadiazol-3-yl)-amide

The title compound, white solid, m.p. 186° C. and MS: m/e=307 (M⁺) wasprepared in accordance with the general method of example 44a from5-methyl-[1,2,4]oxadiazol-3-ylamine and 9H-xanthene-carboxylic acidchloride.

Table 1 sets for the the substituents for each compound of thepreviously described Examples

TABLE 1 B

A¹A² X R¹ R² Z Y R³ heterocycle Expl. phenyl H/H H H O O

— 1 phenyl H/H H H O O

— 2 phenyl H/H H H O O

— 3 phenyl H/H H H O O

— 4 phenyl H/H H H O O

— 5 phenyl O H H O O

— 6 phenyl O H Br O O

— 7 phenyl O H H O O

— 8 phenyl H/H H H O O

— 9 phenyl H/H H H O O

— 10 phenyl H/H H H O O

— 11 phenyl H/H H H O O

— 12 phenyl H/H H H O O

— 13 phenyl H/H H H O O

— 14 phenyl H/H H H O O

— 15 phenyl H/H H H O O

— 16 phenyl H/H H H O O

— 17 phenyl H/H H H O O

— 18 phenyl H/H H H O O

— 19 phenyl H/H H H O O

— 20 phenyl H/H H H O O

— 21 phenyl H/H H H O O

— 22 phenyl H/H CH₃ H O O

— 23 phenyl H/H CH₃ H O O

— 24 phenyl H/H CH₃ H O O

— 25 phenyl H/H CH₃ H O O

— 26 phenyl H/H CH₃ H O O

— 27 phenyl H/H CH₃ H O O

— 28 phenyl H/H CH₃ H O O

— 29 phenyl S H H O O

— 30 phenyl S H H — — —

31 phenyl S H H O O

— 32 phenyl O H H — — —

33 phenyl H/H H H O O

— 34 phenyl H/H H H O S

— 35 phenyl H/H H 3- CF₃ 5-Cl O O

— 36 pyridyl/ phenyl O H H O O

— 37 phenyl O H CF₃ in A2 O O

— 38 phenyl H/H H H O a bond

— 39 phenyl O H H O a bond

— 40 phenyl H/H H H O a bond

— 41 phenyl H/H H H O a bond

— 42 phenyl H/H H H O a bond

— 43 phenyl O H H — — —

44 phenyl H/H H H — — —

45 phenyl O H H — — —

46 phenyl H/H H H — — —

47 phenyl O H H — — —

48 phenyl H/H H H — — —

49 phenyl O H H — — —

50 phenyl H/H H H — — —

51 phenyl O H H — — —

52 phenyl H/H H H — — —

53 phenyl O H H — — —

54 phenyl H/H H H — — —

55 phenyl O H H — — —

56 phenyl H/H H H — — —

57 phenyl O H H — — —

58 phenyl H/H H H — — —

59 phenyl O H H — — —

60 phenyl H/H H H — — —

61 phenyl O H H — — —

62 phenyl H/H H H — — —

63 phenyl O H H — — —

64 phenyl H/H H H — — —

65 phenyl O H H — — —

66 phenyl H/H H H — — —

67 phenyl O H H — — —

68 phenyl H/H H H — — —

69 phenyl H/H H H — — —

70 phenyl O H H — — —

71 phenyl H/H H H — — —

72 phenyl O H H — — —

73 phenyl H/H H H — — —

74 phenyl O H H — — —

75 H/H for X in the above Table 1 denotes two hydrogen atoms, notforming a brigde.

EXAMPLE A

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose  95 White corn starch 35 Polyvinylpyrrolidone  8 Na carboxymethylstarch  10 Magnesiumstearate  2 Tablet weight 250

EXAMPLE B

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch 64 Polyvinylpyrrolidone  12 Na carboxymethylstarch  20 Magnesiumstearate  4 Tablet weight 400

EXAMPLE C

Capsules of the following composition are produced:

mg/Capsule Active ingredient  50 Crystalline. lactose  60Microcrystalline cellulose  34 Talc  5 Magnesium stearate  1 Capsulefill weight 150

The active ingredient having a suitable particle size, the crystallinelactose and the microcrystalline cellulose are homogeneously mixed withone another, sieved and thereafter talc and magnesium stearate areadmixed. The final mixture is filled into hard gelatine capsules ofsuitable size.

What is claimed is:
 1. A compound, 9H-xanthene-9-carboxylic acidoxazol-2-yl-amide.
 2. A compound, 9H-xanthene-9-carboxylic acid(5-propyl-[1,3,4]oxadiazol-2-yl)-amide.
 3. A compound,9H-xanthene-9-carboxylic acid (5-ethyl-oxazol-2-yl)-amide.
 4. Acompound, 9H-xanthene-9-carboxylic acid (5-methyl-oxazol-2-yl)-amide. 5.A compound, 9H-xanthene-9-carboxylic acid (5-propyl-oxazol-2-yl)-amide.6. A compound, 9H-xanthene-9-carboxylic acid(5-ethyl-[1,3,4]oxadiazol-2-yl)-amide.
 7. A compound,9H-xanthene-9-carboxylic acid(5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-amide.
 8. A compound,9H-xanthene-9-carboxylic acid (4-methyl-oxazol-2-yl)-amide.
 9. Acompound, 9H-xanthene-9-carboxylic acid(3-methyl-[1,2,4]oxadiazol-5-yl)-amide.
 10. A compound,9H-Xanthene-9-carboxylic acid(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-amide.
 11. A compound,9H-Xanthene-9-carboxylic acid(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-amide.
 12. A compound,9H-xanthene-9-carboxylic acid(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-amide.
 13. A compound,9H-xanthene-9-carboxylic acid (5-methyl-[1,2,4]oxadiazol-3-yl)-amide.14. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound according of formula I

wherein R¹ is hydrogen or lower alkyl; R², R^(2′) are, independentlyfrom each other, hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; X is O or S; A¹/A² are, independently from each other,phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; Bis a 5-membered heterocyclic group of formulae

 wherein R⁴ and R⁵ are, independently, hydrogen, lower alkyl, loweralkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with theproviso that at least one of R⁴ or R⁵ has to be hydrogen; or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 15. A method of treating neurological disorders in amammal comprising administering to said mammal a compound of the formulaI

wherein R¹ is hydrogen or lower alkyl; R², R^(2′) are, independentlyfrom each other, hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; X is O or S; A¹/A² are, independently from each other,phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; Bis a 5-membered heterocyclic group of formulae

 wherein R⁴ and R⁵ are, independently, hydrogen, lower alkyl, loweralkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with theproviso that at least one of R⁴ or R⁵ has to be hydrogen; or apharmaceutically acceptable salt thereof.
 16. A compound of formula

wherein R¹ are hydrogen or lower alkyl; R², R^(2′) are, independentlyfrom each other, hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl; X signifies O or S; A¹/A² are, independently from eachother, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogenatoms; B is a 5-membered heterocyclic group of formulae

 wherein R⁴ and R⁵ are each, independently, hydrogen, lower alkyl, loweralkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with theproviso that at least one of R⁴ or R⁵ has to be hydrogen; or apharmaceutically acceptable salt thereof.
 17. The compound of claim 16having the formula

wherein R¹ is hydrogen; R², R^(2′) are hydrogen; X is O; A¹/A² arephenyl; B is a 5-membered heterocyclic group of formulae

 wherein R⁴ and R⁵ are each hydrogen, lower alkyl, lower alkoxy,cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the provisothat at least one of R⁴ or R⁵ has to be hydrogen; or a pharmaceuticallyacceptable salt thereof.
 18. A compound, 9H-Xanthene-9-carboxylic acid[1,3,4]oxadiazol-2-ylamide.
 19. A compound, 9H-Xanthene-9-carboxylicacid (5-methyl-[1,3,4]oxadiazol-2-yl)-amide.
 20. A compound,9H-Xanthene-9-carboxylic acid[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amide.
 21. A compound,9H-Xanthene-9-carboxylic acid(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-amide.
 22. The pharmaceuticalcomposition of claim 15 further comprising a therapeutically effectiveamount of the compound according of formula I

wherein R¹ is hydrogen; R², R^(2′) are hydrogen, X is O; A¹/A² arephenyl; B is a 5-membered heterocyclic group of formulae

 wherein R⁴ and R⁵ are each hydrogen, lower alkyl, lower alkoxy,cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the provisothat at least one of R⁴ or R⁵ has to be hydrogen; or a pharmaceuticallyacceptable salt and a pharmaceutically acceptable carrier.
 23. A processfor the manufacture of a compound according to claim 1 comprisingreacting a compound of formula

with a heterocyclic compound of formula B—NH₂  IX to give a compound offormula

wherein B is a 5-membered heterocycle of the formulae

and wherein G is a leaving group; R¹ signifies hydrogen or lower alkyl;R², R^(2′) are, independently from each other, hydrogen, lower alkyl,lower alkoxy, halogen or trifluoromethyl; X is O or S; A¹/A² are,independently from each other, phenyl or a 6-membered heterocyclecontaining 1 or 2 nitrogen atoms; B is a 5-membered heterocyclic groupof formulae

 wherein R⁴ and R⁵ are each, independently, hydrogen, lower alkyl, loweralkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with theproviso that at least one of R⁴ or R⁵ has to be hydrogen; or apharmaceutically acceptable salt thereof.